Objectives To investigate the effects of glutamate receptor, ionotropic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) 2 ( GRIA2) rs4260586 and glutamate receptor, ionotropic, AMPA 4 ( GRIA4) rs10736648 single nucleotide polymorphisms (SNPs) on response to antidepressants in Korean patients with major depressive disorder (MDD), and to ascertain whether epistatic interactions might exist between these SNPs. Methods In this retrospective analysis, patients were assessed at hospital admission and discharge using the Montgomery–Åsberg depression rating scale (MADRS). A multiple regression model was employed to investigate the effects of the two SNP variants on clinical/sociodemographic outcomes relating to MDD. Results Out of 145 Korean patients, the presence of both GRIA2 rs4260586 and GRIA4 rs10736648 polymorphisms had no significant association with MADRS improvement scores or other clinical/sociodemographic variables. Conclusions These data potentially suggest a lack of epistatic interaction between GRIA2 and GRIA4 variants, regarding clinical outcomes in patients with MDD. The study was limited by small sample size, use of different antidepressants and incomplete coverage of genes under investigation. Future research should include larger patient samples treated with different antidepressants, analysis of different SNPs and/or investigation of different gene–gene interactions within the glutamatergic system.